Methods of treating pancreatic cancer

ABSTRACT

The present disclosure describes methods of treating pancreatic cancer and limiting over-expression of oncogenes, activating tumor suppressor genes or regulating signaling proteins in patients comprising administering compounds and pharmaceutical combinations as described herein.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/349,217, filed Jun. 13, 2016, U.S.Provisional Application No. 62/382,689, filed Sep. 1, 2016, U.S.Non-Provisional application Ser. No. 15/621,749, filed Jun. 13, 2017,U.S. Non-Provisional application Ser. No. 15/694,363, filed Sep. 1,2017, and U.S. Non-Provisional application Ser. No. 16/266,961, filedFeb. 4, 2019, all of which are incorporated, in their entirety, by thisreference.

FIELD

The present disclosure describes methods of treating pancreatic cancerand limiting over-expression of oncogenes, activating tumor suppressorgenes or regulating signaling proteins in patients comprisingadministering CCR2 chemokine inhibitor compounds and pharmaceuticalcombinations as described herein.

BACKGROUND

Cancer is a significant health problem throughout the world. Althoughadvances have been made in detection and therapy of cancer, no vaccineor other universally successful method for prevention and/or treatmentis currently available.

Current therapies, which are generally based on a combination ofchemotherapy or surgery and radiation, continue to prove inadequate inmany patients.

Located in the upper abdomen in the retroperitoneum, the pancreas isassociated intimately with many major structures including the portalvein, stomach, duodenum, common bile duct and the superior mesentericartery.

Pancreatic cancer is the fifth leading cause of cancer death in theUnited States. It is more common among men, and men between the ages of60 and 70 are most at risk. As the tumor grows, the patients symptomsresult from tumor infiltration of surrounding structure causing pain,nausea, vomiting, weight loss and jaundice. The latter conditionpresents symptoms in no more than one half of the patients.

Once tumor infiltration occurs other structures such as the portal veinbecome affected and this precludes curative resectioning of thepancreas.

Effective treatment of pancreas cancer is delayed frequently for severalmonths. This delay has profound implications, since metastatic spread tothe liver or lymph nodes has been observed at a time of diagnosis in 60%of patients, and this factor diminishes the prospect for long-termsurvival. Also, the carcinoma of the pancreas is asymptomatic in itsearly stage. The most common symptoms at later stage are weight loss,abdominal pain, and jaundice. Weight loss, the causes of which are notfully understood, usually is significant. Jaundice occurs if the cancerblocks the common bile duct. By the time the malignant tumor isidentified, it often has spread (metastasized) to other parts of thebody. The median survival is little more than six months from the timeof diagnosis.

Current therapies for this common and difficult-to-treat disease includesurgery and/or chemotherapy. Often the tumor cannot be removed bysurgery, either because it has invaded vital structures that cannot beremoved or because it has spread to distant sites.

Accordingly, there is a need in the art for improved treating primaryand metastatic pancreatic cancers.

FIGURES

FIG. 1 represents the mean plasma concentration of Compound Ib followingi.v. in dog dosing of Compound Ib.

FIG. 2 represents the mean plasma concentration of Compound Ib followingp.o. dosing in dog of Compound Ib.

SUMMARY

The present disclosure provides compounds that modulate CCR2 chemokineligand activity and can be used in methods of treating pancreaticcancer. Accordingly, the compounds of the present disclosure arecompounds that modulate at least one function or characteristic ofmammalian CCR2, for example, a human CCR2 protein.

Thus, the present disclosure describes methods of treating pancreaticcancer in patients including administering the compounds andpharmaceutical combinations as described herein. Also described aremethods of limiting over-expression of oncogenes, activating tumorsuppressor genes, and regulating signaling proteins that includeadministering to a patient in need thereof an effective amount of any ofthe compounds or pharmaceutical combinations as described herein.

One embodiment of the present disclosure includes a method of treatingpancreatic cancer in a patient that includes administering to thepatient in need thereof an effective amount of a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; and each of A¹, A², and A³is —CH— or —N—, where at least one of A¹, A², or A³ is —N—. In oneembodiment, R¹ is halogen or methyl; R² is halogen or C₁₋₆ haloalkyl; R³is halogen or C₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—; A²is —CH—; and A³ is —N—. In one embodiment, R¹ is halogen or methyl; R²is C₁₋₆ haloalkyl; R³ is halogen or C₁₋₃ alkyl; R⁴ is hydrogen; n is 0;A¹ is —CH— or —N—; A² is —CH—; and A³ is —N—. In one embodiment, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound is the compound of Formula Ib:

or a pharmaceutically acceptable salt thereof. In one embodiment, thepancreatic cancer is Stage I, II, III, or IV. In one embodiment, thetreatment provides one or more of a decrease in tumor size, asuppression or decrease in tumor growth, no new tumor formation, adecrease in new tumor formation, an increase in survival orprogression-free survival, no metastases, an increase in treatmentoptions, delay in time from surgery to recurrence, reduction injaundice, suppression of spread to liver, reduction in pain, improvedappetite, improved digestion, reduction of gallbladder size, and reducedincidence of blood clots. In one embodiment, the patient achieves acomplete response. In one embodiment, the patient achieves a partialresponse. In one embodiment, the patient achieves stable disease. In oneembodiment, the patient achieves a slower progressive disease. In oneembodiment, the patient suffers from one or more of pancreaticadenocarcinoma, non-resectable pancreatic cancer, locally advancedpancreatic cancer, borderline resectable pancreatic cancer, locallyadvanced pancreatic ductal adenocarcinoma, borderline resectablepancreatic ductal adenocarcinoma, metastatic pancreatic cancer,chemotherapy-resistant pancreatic cancer, pancreatic ductaladenocarcinoma, squamous pancreatic cancer, pancreatic progenitor,immunogenic pancreatic cancer, aberrantly differentiated endocrineexocrine (ADEX) tumors, an exocrine pancreatic cancer, pancreaticintraepithelial neoplasia, intraductal papillary mucinous neoplasms,mucinous cystic neoplasms, mucinous pancreas cancer, adenosquamouscarcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloidcarcinoma, undifferentiated carcinoma, undifferentiated carcinomas withosteoclast-like giant cells, a pancreatic cystic neoplasm, an islet celltumor, a pancreas endrocrine tumor, or a pancreatic neuroendrocrinetumor. In one embodiment, the compound of Formula I is provided as apharmaceutical composition for oral administration. In one embodiment,the compound is administered once a day. In one embodiment, the compoundis administered twice a day. In one embodiment, the method includesadministering to the patient one or more additional therapeuticcompounds. In one embodiment, the one or more additional therapeuticcompound is selected from one or more of a Btk tyrosine kinaseinhibitor, an Erbb2 tyrosine kinase receptor inhibitor; an Erbb4tyrosine kinase receptor inhibitor, an mTOR inhibitor, a thymidylatesynthase inhibitor, an EGFR tyrosine kinase receptor inhibitor, anepidermal growth factor antagonist, a Fyn tyrosine kinase inhibitor, akit tyrosine kinase inhibitor, a Lyn tyrosine kinase inhibitor, a NKcell receptor modulator, a PDGF receptor antagonist, a PARP inhibitor, apoly ADP ribose polymerase inhibitor, a poly ADP ribose polymerase 1inhibitor, a poly ADP ribose polymerase 2 inhibitor, a poly ADP ribosepolymerase 3 inhibitor, a galactosyltransferase modulator, adihydropyrimidine dehydrogenase inhibitor, an orotatephosphoribosyltransferase inhibitor, a telomerase modulator, a mucin 1inhibitor, a mucin inhibitor, a secretin agonist, a TNF relatedapoptosis inducing ligand modulator, an IL17 gene stimulator, aninterleukin 17E ligand, a neurokinin receptor agonist, a cyclin G1inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor,a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5 protein kinaseinhibitor, a connective tissue growth factor ligand inhibitor, a notch-2receptor antagonist, a notch-3 receptor antagonist, a hyaluronidasestimulator, a MEK-1 protein kinase inhibitor; MEK-2 protein kinaseinhibitor, a GM-CSF receptor modulator; TNF alpha ligand modulator, amesothelin modulator, an asparaginase stimulator, a caspase-3stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, a hedgehogprotein inhibitor; smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compounds is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,metronidazole, Gleevec, Avastin, Vectibix, abarelix, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine,anastrozole, arsenic trioxide, asparaginase, azacitidine, AZD9291, BCGLive, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib,busulfan, calusterone, capecitabine, camptothecin, carboplatin,carmustine, celecoxib, cetuximab, chlorambucil, cladribine, clofarabine,cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa,daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral),doxorubicin hydrochloride, dromostanolone propionate, epirubicin,epoetin alfa, estramustine, etoposide phosphate, etoposide, exemestane,filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.

One embodiment includes a method of treating pancreatic cancer in apatient including administering to the patient in need thereof aneffective amount of a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof. In one embodiment, thepancreatic cancer is Stage I, II, III, or IV. In one embodiment, thetreatment provides one or more of a decrease in tumor size, asuppression or decrease of tumor growth, no new tumor formation, adecrease in new tumor formation, an increase in survival orprogression-free survival, no metastases, increase in treatment options,delay in time from surgery to recurrence, reduction in jaundice,suppression of spread to liver, reduction in pain, improved appetite,improved digestion, reduction of gallbladder size, and reduced incidenceof blood clots. In one embodiment, the patient achieves a completeresponse. In one embodiment, the patient achieves a partial response. Inone embodiment, the patient achieves stable disease. In one embodiment,the patient achieves a slower progressive disease. In one embodiment,the patient suffers from pancreatic adenocarcinoma, non-resectablepancreatic cancer, locally advanced pancreatic cancer, borderlineresectable pancreatic cancer, locally advanced pancreatic ductaladenocarcinoma, borderline resectable pancreatic ductal adenocarcinoma,metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer,pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreaticprogenitor, immunogenic pancreatic cancer, aberrantly differentiatedendocrine exocrine (ADEX) tumors, an exocrine pancreatic cancer,pancreatic intraepithelial neoplasia, intraductal papillary mucinousneoplasms, mucinous cystic neoplasms, mucinous pancreas cancer,adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma,colloid carcinoma, undifferentiated carcinoma, undifferentiatedcarcinomas with osteoclast-like giant cells, a pancreatic cysticneoplasm, an islet cell tumor, a pancreas endrocrine tumor, or apancreatic neuroendrocrine tumor. In one embodiment, the compound ofFormula Ib is provided as a pharmaceutical composition for oraladministration. In one embodiment, the compound is administered once aday. In one embodiment, the compound is administered twice a day. In oneembodiment, the effective amount is from 50 mg to 300 mg. In oneembodiment, the effective amount is 150 mg. In one embodiment, themethod further includes administering to the patient one or moreadditional therapeutic compounds. In one embodiment, the one or moreadditional therapeutic compounds is selected from one or more of a Btktyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptor inhibitor;an Erbb4 tyrosine kinase receptor inhibitor, an mTOR inhibitor, athymidylate synthase inhibitor, an EGFR tyrosine kinase receptorinhibitor, an Epidermal growth factor antagonist, a Fyn tyrosine kinaseinhibitor, a kit tyrosine kinase inhibitor, a Lyn tyrosine kinaseinhibitor, a NK cell receptor modulator, a PDGF receptor antagonist, aPARP inhibitor, a poly ADP ribose polymerase inhibitor, a poly ADPribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2 inhibitor,a poly ADP ribose polymerase 3 inhibitor, a galactosyltransferasemodulator, a dihydropyrimidine dehydrogenase inhibitor, an orotatephosphoribosyltransferase inhibitor, a telomerase modulator, a mucin 1inhibitor, a mucin inhibitor, a secretin agonist, a TNF relatedapoptosis inducing ligand modulator, an IL17 gene stimulator, aninterleukin 17E ligand, a Neurokinin receptor agonist, a cyclin G1inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor,a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5 protein kinaseinhibitor, a connective tissue growth factor ligand inhibitor, a notch-2receptor antagonist, a notch-3 receptor antagonist, a hyaluronidasestimulator, a MEK-1 protein kinase inhibitor; MEK-2 protein kinaseinhibitor, a GM-CSF receptor modulator; TNF alpha ligand modulator, amesothelin modulator, an asparaginase stimulator, a caspase-3stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, a hedgehogprotein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.

One embodiment of the present disclosure includes a pharmaceuticalcombination for comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; each of A¹, A², and A³ is—CH— or —N— where at least one of A¹, A², or A³ is —N—; and one or moreadditional therapeutic compounds. In one embodiment, the one or moreadditional therapeutic compound is selected from one or more of a Btktyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptor inhibitor;an Erbb4 tyrosine kinase receptor inhibitor, an mTOR inhibitor, athymidylate synthase inhibitor, an EGFR tyrosine kinase receptorinhibitor, an epidermal growth factor antagonist, a Fyn tyrosine kinaseinhibitor, a kit tyrosine kinase inhibitor, a Lyn tyrosine kinaseinhibitor, a NK cell receptor modulator, a PDGF receptor antagonist, aPARP inhibitor, a poly ADP ribose polymerase inhibitor, a poly ADPribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2 inhibitor,a poly ADP ribose polymerase 3 inhibitor, a galactosyltransferasemodulator, a dihydropyrimidine dehydrogenase inhibitor, an orotatephosphoribosyltransferase inhibitor, a telomerase modulator, a mucin 1inhibitor, a mucin inhibitor, a secretin agonist, a TNF relatedapoptosis inducing ligand modulator, an IL17 gene stimulator, aninterleukin 17E ligand, a neurokinin receptor agonist, a cyclin G1inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor,a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5 protein kinaseinhibitor, a connective tissue growth factor ligand inhibitor, a notch-2receptor antagonist, a notch-3 receptor antagonist, a hyaluronidasestimulator, a MEK-1 protein kinase inhibitor; MEK-2 protein kinaseinhibitor, a GM-CSF receptor modulator; TNF alpha ligand modulator, amesothelin modulator, an asparaginase stimulator, a caspase-3stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, a hedgehogprotein inhibitor; smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, novaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompound are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compound is gemcitabine and nab-paclitaxel.In one embodiment, the combination comprises a fixed dose combination orseparate doses. In one embodiment, R¹ is halogen or methyl; R² ishalogen or C₁₋₆ haloalkyl; R³ is halogen or C₁₋₆ alkyl; R⁴ is hydrogen;n is 0; A¹ is —CH— or —N—; A² is —CH—; and A³ is —N—. In one embodiment,R¹ is halogen or methyl; R² is C₁₋₃ haloalkyl; R³ is halogen or C₁₋₃alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—; A² is —CH—; and A³ is—N—. In one embodiment, the combination is selected from:

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound is the compound of Formula Ib:

or a pharmaceutically acceptable salt thereof.

One embodiment includes a method of limiting over-expression ofoncogenes, activating tumor suppressor genes, or regulating signalingproteins comprising administering to a patient in need thereof aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; and each of A¹, A², and A³is —CH— or —N—, where at least one of A¹, A², or A³ is —N—. In oneembodiment, R¹ is halogen or methyl; R² is halogen or C₁₋₆ haloalkyl; R³is halogen or C₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—; A²is —CH—; and A³ is —N—. In one embodiment, R¹ is halogen or methyl; R²is C₁₋₃ haloalkyl; R³ is halogen or C₁₋₃ alkyl; R⁴ is hydrogen; n is 0;A¹ is —CH— or —N—; A² is —CH—; and A³ is —N—. In one embodiment, thecompound is selected from:

or a pharmaceutically acceptable salt thereof. In an embodiment, thecompound is the compound of Formula 1b:

or a pharmaceutically acceptable salt thereof. In one embodiment, theover-expression of oncogenes, inactivation tumor suppressor genes or thederegulation of various signaling proteins resulted in diagnosis ofpancreatic cancer for the patient. In one embodiment, the patient hasbeen diagnosed with pancreatic adenocarcinoma, non-resectable pancreaticcancer, locally advanced pancreatic cancer, borderline resectablepancreatic cancer, locally advanced pancreatic ductal adenocarcinoma,borderline resectable pancreatic ductal adenocarcinoma, metastaticpancreatic cancer, chemotherapy-resistant pancreatic cancer, squamouspancreatic cancer, pancreatic progenitor, immunogenic pancreatic cancer,aberrantly differentiated endocrine exocrine (ADEX) tumors, pancreaticductal adenocarcinoma. an exocrine pancreatic cancer, pancreaticintraepithelial neoplasia, intraductal papillary mucinous neoplasms,mucinous cystic neoplasms, mucinous pancreas cancer, adenosquamouscarcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloidcarcinoma, undifferentiated carcinoma, undifferentiated carcinomas withosteoclast-like giant cells, a pancreatic cystic neoplasm, an islet celltumor, a pancreas endrocrine tumor, or a pancreatic neuroendrocrinetumor. In one embodiment, the compound of Formula I is provided as apharmaceutical composition for oral administration. In one embodiment,the patient achieves a complete response. In one embodiment, the patientachieves a partial response. In one embodiment, the patient achievesstable disease. In one embodiment, the patient achieves a slowerprogressive disease. In one embodiment, the compound is administeredonce a day. In one embodiment, the compound is administered twice a day.In one embodiment, the method includes administering to the patient oneor more additional therapeutic compounds. In one embodiment, the one ormore additional therapeutic compound is selected from one or more of aBtk tyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptorinhibitor; an Erbb4 tyrosine kinase receptor inhibitor, an mTORinhibitor, a thymidylate synthase inhibitor, an EGFR tyrosine kinasereceptor inhibitor, an epidermal growth factor antagonist, a Fyntyrosine kinase inhibitor, a kit tyrosine kinase inhibitor, a Lyntyrosine kinase inhibitor, a NK cell receptor modulator, a PDGF receptorantagonist, a PARP inhibitor, a poly ADP ribose polymerase inhibitor, apoly ADP ribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2inhibitor, a poly ADP ribose polymerase 3 inhibitor, agalactosyltransferase modulator, a dihydropyrimidine dehydrogenaseinhibitor, an orotate phosphoribosyltransferase inhibitor, a telomerasemodulator, a mucin 1 inhibitor, a mucin inhibitor, a secretin agonist, aTNF related apoptosis inducing ligand modulator, an IL17 genestimulator, an interleukin 17E ligand, a neurokinin receptor agonist, acyclin G1 inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1inhibitor, a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5protein kinase inhibitor, a connective tissue growth factor ligandinhibitor, a notch-2 receptor antagonist, a notch-3 receptor antagonist,a hyaluronidase stimulator, a MEK-1 protein kinase inhibitor; MEK-2protein kinase inhibitor, a GM-CSF receptor modulator; TNF alpha ligandmodulator, a mesothelin modulator, an asparaginase stimulator, acaspase-3 stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, ahedgehog protein inhibitor; smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.

One embodiment includes a method for controlling an adenocarcinoma in apatient that includes administering to the patient in need thereof aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof. In one embodiment, R¹ ishalogen or C₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, orC₁₋₆ alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ isindependently C₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; and each ofA¹, A², and A³ is —CH— or —N—, where at least one of A¹, A², or A³ is—N—. In one embodiment, R¹ is halogen or methyl; R² is C₁₋₃ haloalkyl;R³ is halogen or C₁₋₃ alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—;A² is —CH—; and A³ is —N—. In one embodiment, the compound is selectedfrom

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound is

or a pharmaceutically acceptable salt thereof. In one embodiment, theadenocarcinoma is pancreatic adenocarcinoma. In one embodiment, thepatient achieves a complete response. In one embodiment, the patientachieves a partial response. In one embodiment, the patient achievesstable disease. In one embodiment, the patient achieves a slowerprogressive disease. In one embodiment, the patient achieves a clinicalbenefit. In one embodiment, the clinical benefit is one or more ofdecrease in tumor size, suppression or decrease of tumor growth, delayedtime to progression, no new tumor or lesion, a decrease in new tumorformation, an increase in survival or progression-free survival, nometastases, increase in treatment options, delay in time from surgery torecurrence, reduction in jaundice, suppression of spread to liver,reduction in pain, improved appetite, improved digestion, reduction ofgallbladder size, and reduced incidence of blood clots. In oneembodiment, the compound of Formula I is provided as a pharmaceuticalcomposition for oral administration. In one embodiment, the compound isadministered once a day. In one embodiment, the compound is administeredtwice a day. In one embodiment, the effective amount is from 50 mg to300 mg. In one embodiment, the effective amount is 150 mg. In oneembodiment, the method further comprises administering to the patientone or more additional therapeutic compound. In one embodiment, the oneor more additional therapeutic compound is selected from one or more ofa Btk tyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptorinhibitor; an Erbb4 tyrosine kinase receptor inhibitor, an mTORinhibitor, a thymidylate synthase inhibitor, an EGFR tyrosine kinasereceptor inhibitor, an Epidermal growth factor antagonist, a Fyntyrosine kinase inhibitor, a kit tyrosine kinase inhibitor, a Lyntyrosine kinase inhibitor, a NK cell receptor modulator, a PDGF receptorantagonist, a PARP inhibitor, a poly ADP ribose polymerase inhibitor, apoly ADP ribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2inhibitor, a poly ADP ribose polymerase 3 inhibitor, agalactosyltransferase modulator, a dihydropyrimidine dehydrogenaseinhibitor, an orotate phosphoribosyltransferase inhibitor, a telomerasemodulator, a mucin 1 inhibitor, a mucin inhibitor, a secretin agonist, aTNF related apoptosis inducing ligand modulator, an IL17 genestimulator, an interleukin 17E ligand, a Neurokinin receptor agonist, acyclin G1 inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1inhibitor, a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5protein kinase inhibitor, a connective tissue growth factor ligandinhibitor, a notch-2 receptor antagonist, a notch-3 receptor antagonist,a hyaluronidase stimulator, a MEK-1 protein kinase inhibitor; MEK-2protein kinase inhibitor, a GM-CSF receptor modulator; TNF alpha ligandmodulator, a mesothelin modulator, an asparaginase stimulator, acaspase-3 stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, ahedgehog protein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wlms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.

DETAILED DESCRIPTION

The present disclosure is directed to methods of treating pancreaticcancer in patients by administering the compounds and pharmaceuticalcombinations as described herein. Also described are methods of limitingover-expression of oncogenes, activating tumor suppressor genes, orregulating signaling proteins comprising administering to a patient inneed thereof an effective amount of any of the compounds orpharmaceutical combinations as described herein. Accordingly, thepresent disclosure describes compounds which modulate at least onefunction or characteristic of mammalian CCR2, for example, a human CCR2protein.

Abbreviations and Definitions

The following definitions are meant to clarify, but not limit, the termsdefined. If a particular term used herein is not specifically defined,such term should not be considered indefinite. Rather, terms are usedwithin their accepted meanings by those of skill in the art.

“Alkyl” by itself or as part of another substituent refers to ahydrocarbon group which may be linear, cyclic, or branched or acombination thereof having the number of carbon atoms designated (i.e.,C₁₋₈ means one to eight carbon atoms). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

“Alkoxy” refers to —O-alkyl. Examples of an alkoxy group includemethoxy, ethoxy, n-propoxy etc.

“Clinical benefit” refers to a phrase used by doctors and/or clinicianstreating cancer. The term encompasses any appreciated or perceivedbenefit encountered by a patient during therapy. As used herein, theterm includes but is not limited to one or more of clinical benefit isone or more of decrease in tumor size, suppression or decrease of tumorgrowth, delayed time to progression, no new tumor or lesion, a decreasein new tumor formation, an increase in survival or progression-freesurvival, no metastases, increase in treatment options, delay in timefrom surgery to recurrence, reduction in jaundice, suppression of spreadto liver, reduction in pain, improved appetite, improved digestion,reduction of gallbladder size, and reduced incidence of blood clots.

“Complete response” refers to a response which results in completeeradication of noninvasive or invasive cancers.

“FOLFIRINOX” refers to a chemotherapy regimen for treatment of advancedpancreatic cancer. It is made up of the following four drugs:

-   -   a) FOL—folinic acid (leucovorin), a vitamin B derivative that        modulates/potentiates/reduces the side effects of fluorouracil;    -   b) F—fluorouracil (5-FU), a pyrimidine analog and antimetabolite        which incorporates into the DNA molecule and stops DNA        synthesis;    -   c) IRIN—irinotecan (Camptosar), a topoisomerase inhibitor, which        prevents DNA from uncoiling and duplicating; and    -   d) OX—oxaliplatin (Eloxatin), a platinum-based antineoplastic        agent, which inhibits DNA repair and/or DNA synthesis.

“Halo” or “halogen”, by itself or as part of a substituent refers to achlorine, bromine, iodine, or fluorine atom.

“Haloalkyl”, as a substituted alkyl group, refers to a monohaloalkyl orpolyhaloalkyl group, most typically substituted with from 1-3 halogenatoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyland the like.

“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S)and silicon (Si).

“Partial response” refers to a response which results in at least 30%reduction in tumor size as compared to baseline, namely prior toadministration of compound.

“Pharmaceutically acceptable” carrier, diluent, or excipient is acarrier, diluent, or excipient compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

“Pharmaceutically acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically acceptable inorganic or organic basesand from pharmaceutically acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present disclosure containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present disclosure containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent. Saltsderived from pharmaceutically acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present disclosure contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

“Progressive disease” refers to at least 20% growth in the size of atumor or spread of a tumor since the beginning of treatment.

“Salt thereof” refers to either a compound formed when the hydrogen ofan acid is replaced by a cation, such as a metal cation or an organiccation and the like or a compound formed from a base protonated with acounter-ion. Preferably, the salt is a pharmaceutically-acceptable salt,although this is not required for salts of intermediate compounds whichare not intended for administration to a patient.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

“Stable disease” refers to cancer that is neither increasing nordecreasing in extent or severity.

“Therapeutically effective amount” refers to an amount sufficient toeffect treatment when administered to a patient in need of treatment.

“Treating” or “treatment” as used herein refers to the treating ortreatment of a disease or medical condition (such as a viral, bacterialor fungal infection or other infectious diseases, as well as autoimmuneor inflammatory conditions) in a patient, such as a mammal (particularlya human or a companion animal) which includes ameliorating the diseaseor medical condition, i.e., eliminating or causing regression of thedisease or medical condition in a patient; suppressing the disease ormedical condition, i.e., slowing or arresting the development of thedisease or medical condition in a patient; or alleviating the symptomsof the disease or medical condition in a patient.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,both solvated forms and unsolvated forms are intended to be encompassedwithin the scope of the present disclosure. Certain compounds of thepresent disclosure may exist in multiple crystalline or amorphous forms(i.e., as polymorphs). In general, all physical forms are equivalent forthe uses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

It will be apparent to one skilled in the art that certain compounds ofthe present disclosure may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of thedisclosure. Certain compounds of the present disclosure possessasymmetric carbon atoms (optical centers) or double bonds; theracemates, diastereomers, geometric isomers and individual isomers(e.g., separate enantiomers) are all intended to be encompassed withinthe scope of the present disclosure. The compounds of the presentdisclosure may also contain unnatural proportions of atomic isotopes atone or more of the atoms that constitute such compounds. Unnaturalproportions of an isotope may be defined as ranging from the amountfound in nature to an amount consisting of 100% of the atom in question.For example, the compounds may incorporate radioactive isotopes, such asfor example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C), ornon-radioactive isotopes, such as deuterium (²H) or carbon-13 (¹³C).Such isotopic variations can provide additional utilities to thosedescribed elsewhere within this application. For instance, isotopicvariants of the compounds of the invention may find additional utility,including but not limited to, as diagnostic and/or imaging reagents, oras cytotoxic/radiotoxic therapeutic agents. Additionally, isotopicvariants of the compounds of the invention can have alteredpharmacokinetic and pharmacodynamic characteristics which can contributeto enhanced safety, tolerability or efficacy during treatment. Allisotopic variations of the compounds of the present invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe present disclosure.

Compounds that Modulate CCR2 Activity

The present disclosure provides compounds that modulate CCR2 activity.Chemokine receptors are integral membrane proteins which interact withan extracellular ligand, such as a chemokine, and mediate a cellularresponse to the ligand, e.g., chemotaxis, increased intracellularcalcium ion concentration, etc. Therefore, modulation of a chemokinereceptor function, e.g., interference with a chemokine receptor ligandinteraction, will modulate a chemokine receptor mediated response, andtreat or prevent a chemokine receptor mediated condition or disease.Modulation of a chemokine receptor function includes both inducement andinhibition of the function. The type of modulation accomplished willdepend on the characteristics of the compound, i.e., antagonist or full,partial or inverse agonist.

Without intending to be bound by any particular theory, it is believedthat the compounds provided herein interfere with the interactionbetween a chemokine receptor and one or more cognate ligands. Inparticular, it is believed that the compounds interfere with theinteraction between CCR2 and a CCR2 ligand, such as MCP-1. Compoundscontemplated by the disclosure include, but are not limited to, theexemplary compounds provided herein and salts thereof.

The compounds of the disclosure are thought to interfere withinappropriate T-cell trafficking by specifically modulating orinhibiting a chemokine receptor function. Compounds contemplated by thedisclosure include, but are not limited to, the exemplary compoundsprovided herein and salts thereof.

Compounds

One embodiment of the present disclosure includes the compound ofFormula I, or salts thereof:

R¹ is halogen or C₁₋₆ alkyl;

R² is selected from the group comprising hydrogen, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or —CN;

R³ is selected from the group comprising hydrogen, halogen or C₁₋₆alkyl;

R⁴ if present is selected from the group comprising hydrogen, halogen,or C₁₋₆ alkyl;

each R⁵ if present is independently selected from the group comprisingC₁₋₆ alkyl, —OH, or —NH₂;

n is 0, 1, 2, or 3; and

each of A¹, A² and A³ is —CH— or —N—, where at least one of A¹, A² or A³is —N—.

In as much as any composition described herein defines any atom asnitrogen, i.e. for A¹, A² and A³, the person of ordinary skill in theart should understand that the nitrogen atom would maintain itsaromaticity. Nothing in this disclosure should be construed otherwise.

In one embodiment, R¹ is halogen or methyl; R2 is halogen or C₁₋₆haloalkyl; R³ is halogen or C₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹ is—CH— or —N; A² is —CH; and A³ is —N—. In one embodiment, R¹ is halogenor methyl; R² is C₁₋₃ haloalkyl; R³ is halogen or C₁₋₃ alkyl; R⁴ ishydrogen; n is 0; A¹ is —CH— or —N—; A² is —CH—; and A³ is —N—. In oneembodiment, the compound is selected from the following formula, orsalts thereof:

In another embodiment, the compound is the compound of Formula 1b, orsalts thereof:

Compositions

Pharmaceutically acceptable compositions can be administered to humansand other animals orally, rectally, parenterally, intracistemally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), bucally, as an oral or nasal spray, or the like.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compound(s),a liquid dosage form may contain inert diluents commonly used in the artsuch as, for example, water or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may be incorporated in an injectable product.The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the disclosure, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisdisclosure with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The compounds of the present disclosure or a pharmaceutically acceptablesalt thereof may be formulated using nanotechnology. Nanoparticles areattractive for medical purposes based on their unique features, such astheir surface to mass ratio being larger than that of other particles,their quantum properties, and their ability to adsorb and carry othercompounds. Nanoparticles may have dimensions below 0.1 μm or 100 nm.Alternatively, a pharmaceutical composition may comprise relativelylarge (size >100 nm) nanoparticles, as needed for loading a sufficientamount of drug onto the particles. In addition, for drug delivery, notonly engineered particles may be used as carrier, but also the drugitself may be formulated at a nanoscale, and then function as its owncarrier. The composition of the engineered nanoparticles may vary.Source materials may be of biological origin like phospholipids, lipids,lactic acid, dextran, chitosan, or have more chemical characteristicslike various polymers, carbon, silica, and metals. Especially in thearea of engineered nanoparticles of polymer origin there is a vast areaof possibilities for the chemical composition. See, for example, Martinset al., Nanoparticle Drug Delivery Systems: Recent Patents andApplications in Nanomedicine, Recent Patents on Nanomedicine, 2013,3(2), pp 1-14.

The compounds of the present disclosure or a pharmaceutically acceptablesalt thereof may also be in microencapsulated form with one or moreexcipients as noted above. The solid dosage forms of tablets, dragees,capsules, pills, and granules can be prepared with coatings and shellssuch as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis disclosure include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this disclosure. Additionally, the disclosurecontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

Methods of Treatment

One embodiment of the present disclosure includes methods for treatingpancreatic cancer in a patient comprising administrating to the patientin need thereof an effective amount of any of the compounds describedherein. In one embodiment, the pancreatic cancer is Stage I, II, III orIV. In one embodiment, the treatment provides one or more of a decreasein tumor size, a suppression or decrease in tumor growth, no new tumorformation, a decrease in new tumor formation, an increase in survival orprogression-free survival, no metastases, an increase in treatmentoptions, delay in time from surgery to recurrence, reduction injaundice, suppression of spread to liver, reduction in pain, improvedappetite, improved digestion, reduction of gallbladder size, and reducedincidence of blood clots. In one embodiment, the patient achieves acomplete response. In one embodiment, the patient achieves a partialresponse. In one embodiment, the patient achieves stable disease. In oneembodiment, the patient achieves a slower progressive disease. In oneembodiment, the patient suffers from one or more of pancreaticadenocarcinoma, non-resectable pancreatic cancer, locally advancedpancreatic cancer, borderline resectable pancreatic cancer, locallyadvanced pancreatic ductal adenocarcinoma, borderline resectablepancreatic ductal adenocarcinoma, metastatic pancreatic cancer,chemotherapy-resistant pancreatic cancer, pancreatic ductaladenocarcinoma, squamous pancreatic cancer, pancreatic progenitor,immunogenic pancreatic cancer, aberrantly differentiated endocrineexocrine (ADEX) tumors, an exocrine pancreatic cancer, pancreaticintraepithelial neoplasia, intraductal papillary mucinous neoplasms,mucinous cystic neoplasms, mucinous pancreas cancer, adenosquamouscarcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloidcarcinoma, undifferentiated carcinoma, undifferentiated carcinomas withosteoclast-like giant cells, a pancreatic cystic neoplasm, an islet celltumor, a pancreas endrocrine tumor, or a pancreatic neuroendrocrinetumor. In one embodiment, the compound of Formula I is provided as apharmaceutical composition for oral administration. In one embodiment,the compound is administered once a day. In one embodiment, the compoundis administered twice a day. In one embodiment, the method furthercomprises administering to the patient one or more additionaltherapeutic compound. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of a Btk tyrosinekinase inhibitor, an Erbb2 tyrosine kinase receptor inhibitor; an Erbb4tyrosine kinase receptor inhibitor, an mTOR inhibitor, a thymidylatesynthase inhibitor, an EGFR tyrosine kinase receptor inhibitor, anepidermal growth factor antagonist, a Fyn tyrosine kinase inhibitor, akit tyrosine kinase inhibitor, a Lyn tyrosine kinase inhibitor, a NKcell receptor modulator, a PDGF receptor antagonist, a PARP inhibitor, apoly ADP ribose polymerase inhibitor, a poly ADP ribose polymerase 1inhibitor, a poly ADP ribose polymerase 2 inhibitor, a poly ADP ribosepolymerase 3 inhibitor, a galactosyltransferase modulator, adihydropyrimidine dehydrogenase inhibitor, an orotatephosphoribosyltransferase inhibitor, a telomerase modulator, a mucin 1inhibitor, a mucin inhibitor, a secretin agonist, a TNF relatedapoptosis inducing ligand modulator, an IL17 gene stimulator, aninterleukin 17E ligand, a Neurokinin receptor agonist, a cyclin G1inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor,a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5 protein kinaseinhibitor, a connective tissue growth factor ligand inhibitor, a notch-2receptor antagonist, a notch-3 receptor antagonist, a hyaluronidasestimulator, a MEK-1 protein kinase inhibitor; MEK-2 protein kinaseinhibitor, a GM-CSF receptor modulator; TNF alpha ligand modulator, amesothelin modulator, an asparaginase stimulator, a caspase-3stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, a hedgehogprotein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,metronidazole, Gleevec, Avastin, Vectibix, abarelix, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine,anastrozole, arsenic trioxide, asparaginase, azacitidine, AZD9291, BCGLive, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib,busulfan, calusterone, capecitabine, camptothecin, carboplatin,carmustine, celecoxib, cetuximab, chlorambucil, cladribine, clofarabine,cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa,daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral),doxorubicin hydrochloride, dromostanolone propionate, epirubicin,epoetin alfa, estramustine, etoposide phosphate, etoposide, exemestane,filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.

One embodiment of the present disclosure includes a method of treatingpancreatic cancer in a patient comprising administering to the patientin need thereof an effective amount of a compound of Formula Ib:

In one embodiment, the pancreatic cancer is Stage I, II, III, or IV. Inone embodiment, the treatment provides one or more of a decrease intumor size, a suppression or decrease of tumor growth, no new tumorformation, a decrease in new tumor formation, an increase in survival orprogression-free survival, no metastases, increase in treatment options,delay in time from surgery to recurrence, reduction in jaundice,suppression of spread to liver, reduction in pain, improved appetite,improved digestion, reduction of gallbladder size, and reduced incidenceof blood clots. In one embodiment, the patient achieves a completeresponse. In one embodiment, the patient achieves a partial response. Inone embodiment, the patient achieves stable disease. In one embodiment,the patient achieves a slower progressive disease. In one embodiment,the patient suffers from pancreatic adenocarcinoma, locally advancedpancreatic cancer, borderline resectable pancreatic cancer, locallyadvanced pancreatic ductal adenocarcinoma, borderline resectablepancreatic ductal adenocarcinoma, non-resectable pancreatic cancer,metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer,pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreaticprogenitor, immunogenic pancreatic cancer, aberrantly differentiatedendocrine exocrine (ADEX) tumors, an exocrine pancreatic cancer,pancreatic intraepithelial neoplasia, intraductal papillary mucinousneoplasms, mucinous cystic neoplasms, mucinous pancreas cancer,adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma,colloid carcinoma, undifferentiated carcinoma, undifferentiatedcarcinomas with osteoclast-like giant cells, a pancreatic cysticneoplasm, an islet cell tumor, a pancreas endrocrine tumor, or apancreatic neuroendrocrine tumor. In one embodiment, the compound ofFormula Ib is provided as a pharmaceutical composition for oraladministration. In one embodiment, the compound is administered once aday. In one embodiment, the compound of Formula Ib the compound isadministered twice a day. In one embodiment, the effective amount isfrom 50 mg to 300 mg. In one embodiment, the effective amount is 150 mg.In one embodiment, the method further comprises administering to thepatient one or more additional therapeutic compound. In aspect of theembodiment the one or more additional therapeutic compound is selectedfrom one or more of a Btk tyrosine kinase inhibitor, an Erbb2 tyrosinekinase receptor inhibitor; an Erbb4 tyrosine kinase receptor inhibitor,an mTOR inhibitor, a thymidylate synthase inhibitor, an EGFR tyrosinekinase receptor inhibitor, an Epidermal growth factor antagonist, a Fyntyrosine kinase inhibitor, a kit tyrosine kinase inhibitor, a Lyntyrosine kinase inhibitor, a NK cell receptor modulator, a PDGF receptorantagonist, a PARP inhibitor, a poly ADP ribose polymerase inhibitor, apoly ADP ribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2inhibitor, a poly ADP ribose polymerase 3 inhibitor, agalactosyltransferase modulator, a dihydropyrimidine dehydrogenaseinhibitor, an orotate phosphoribosyltransferase inhibitor, a telomerasemodulator, a mucin 1 inhibitor, a mucin inhibitor, a secretin agonist, aTNF related apoptosis inducing ligand modulator, an IL17 genestimulator, an interleukin 17E ligand, a Neurokinin receptor agonist, acyclin G1 inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1inhibitor, a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5protein kinase inhibitor, a connective tissue growth factor ligandinhibitor, a notch-2 receptor antagonist, a notch-3 receptor antagonist,a hyaluronidase stimulator, a MEK-1 protein kinase inhibitor; MEK-2protein kinase inhibitor, a GM-CSF receptor modulator; TNF alpha ligandmodulator, a mesothelin modulator, an asparaginase stimulator, acaspase-3 stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, ahedgehog protein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compound is gemcitabine and nab-paclitaxel.

One embodiment of the present disclosure includes a pharmaceuticalcombination comprising the compound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; each of A¹, A², and A³ is—CH— or —N—, where at least one of A¹, A², or A³ is —N—; and one or moreadditional therapeutic compound. In one embodiment, the one or moreadditional therapeutic compound is selected from one or more ofbavituximab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K,PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207,NovaCaps, trametinib, Atu-027, sonidegib, GRASPA, trabedersen,nastorazepide, Vaccell, oregovomab, istiratumab, refametinib,regorafenib, lapatinib, selumetinib, rucaparib, pelareorep, tarextumab,PEGylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01,GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab,DCVax-Direct, selinexor, glufosfamide, virulizin, yttrium (90Y)clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel. In one embodiment, the combination comprises a fixeddose combination or separate doses. In one aspect of the embodiment, R¹is halogen or methyl; R² is halogen or C₁₋₆ haloalkyl; R³ is halogen orC₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—; A² is —CH—; andA³ is —N—. In one embodiment, R¹ is halogen or methyl; R² is C₁₋₆haloalkyl; R³ is halogen or C₁₋₃ alkyl; R⁴ is hydrogen; n is 0; A¹ is—CH— or —N—; A² is —CH—; and A³ is —N—. In one embodiment, the compoundis selected from the following formulas or salts thereof:

In one embodiment, the compound is the compound of Formula Ib:

In one embodiment, the method comprises administration of thepharmaceutical combination of any one of compounds described herein.

One embodiment of the present disclosure includes a method of limitingover-expression of oncogenes, activating tumor suppressor genes, orregulating signaling proteins comprising administering to a patient inneed thereof an effective amount of the compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁i.alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; and each of A¹, A², and A³is —CH— or —N—, where at least one of A¹, A², or A³ is —N—. In oneembodiment, R¹ is halogen or methyl; R² is halogen or C₁₋₆ haloalkyl; R³is halogen or C₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—; A²is —CH—; and A³ is —N—. In one embodiment, R¹ is halogen or methyl; R²is C₁₋₆ haloalkyl; R³ is halogen or C₁a alkyl; R⁴ is hydrogen; n is 0;A¹ is —CH— or —N—; A² is —CH—; and A³ is —N—. In one embodiment, thecompound is selected from:

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound is the compound of Formula Ib:

or a pharmaceutically acceptable salt thereof. In aspect of theembodiment the over-expression of oncogenes, inactivation tumorsuppressor genes or the deregulation of various signaling proteinsresulted in diagnosis of pancreatic cancer for the patient. In oneembodiment, the patient has been diagnosed with pancreaticadenocarcinoma, non-resectable pancreatic cancer, metastatic pancreaticcancer, chemotherapy-resistant pancreatic cancer, squamous pancreaticcancer, pancreatic progenitor, immunogenic pancreatic cancer, aberrantlydifferentiated endocrine exocrine (ADEX) tumors, pancreatic ductaladenocarcinoma. an exocrine pancreatic cancer, pancreaticintraepithelial neoplasia, intraductal papillary mucinous neoplasms,mucinous cystic neoplasms, mucinous pancreas cancer, adenosquamouscarcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloidcarcinoma, undifferentiated carcinoma, undifferentiated carcinomas withosteoclast-like giant cells, a pancreatic cystic neoplasm, an islet celltumor, a pancreas endrocrine tumor, or a pancreatic neuroendrocrinetumor. In one embodiment, the compound of Formula I is provided as apharmaceutical composition for oral administration. In one embodiment,the patient achieves a complete response. In one embodiment, the patientachieves a partial response. In one embodiment, the patient achievesstable disease. In one embodiment, the patient achieves a slowerprogressive disease. In one embodiment, the compound is administeredonce a day. In one embodiment, the compound is administered twice a day.In one embodiment, the method further comprises administering to thepatient one or more additional therapeutic compound. In one embodiment,the one or more additional therapeutic compound is selected from one ormore of a Btk tyrosine kinase inhibitor, an Erbb2 tyrosine kinasereceptor inhibitor; an Erbb4 tyrosine kinase receptor inhibitor, an mTORinhibitor, a thymidylate synthase inhibitor, an EGFR tyrosine kinasereceptor inhibitor, an Epidermal growth factor antagonist, a Fyntyrosine kinase inhibitor, a kit tyrosine kinase inhibitor, a Lyntyrosine kinase inhibitor, a NK cell receptor modulator, a PDGF receptorantagonist, a PARP inhibitor, a poly ADP ribose polymerase inhibitor, apoly ADP ribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2inhibitor, a poly ADP ribose polymerase 3 inhibitor, agalactosyltransferase modulator, a dihydropyrimidine dehydrogenaseinhibitor, an orotate phosphoribosyltransferase inhibitor, a telomerasemodulator, a mucin 1 inhibitor, a mucin inhibitor, a secretin agonist, aTNF related apoptosis inducing ligand modulator, an IL17 genestimulator, an interleukin 17E ligand, a Neurokinin receptor agonist, acyclin G1 inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1inhibitor, a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5protein kinase inhibitor, a connective tissue growth factor ligandinhibitor, a notch-2 receptor antagonist, a notch-3 receptor antagonist,a hyaluronidase stimulator, a MEK-1 protein kinase inhibitor; MEK-2protein kinase inhibitor, a GM-CSF receptor modulator; TNF alpha ligandmodulator, a mesothelin modulator, an asparaginase stimulator, acaspase-3 stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, ahedgehog protein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.

One embodiment of the present disclosure includes a method forcontrolling an adenocarcinoma in a patient comprising administering tothe patient in need thereof an effective amount the compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; and each of A¹, A², and A³is —CH— or —N—, where at least one of A¹, A², or A³ is —N—. In oneembodiment, R¹ is halogen or methyl; R² is halogen or C₁₋₆ haloalkyl; R³is halogen or C₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹ is —CH— or —N—; A²is —CH—; and A³ is —N—. In one embodiment, R¹ is halogen or methyl; R²is C₁₋₆ haloalkyl; R³ is halogen or C₁a alkyl; R⁴ is hydrogen; n is 0;A¹ is —CH— or —N—; A² is —CH—; and A³ is —N—. In one embodiment, thecompound is selected from:

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound is the compound of Formula Ib:

or a pharmaceutically acceptable salt thereof. In one embodiment, theadenocarcinoma is pancreatic adenocarcinoma. In one embodiment, thepatient achieves a complete response. In one embodiment, the patientachieves a partial response. In one embodiment, the patient achievesstable disease. In one embodiment, the patient achieves a slowerprogressive disease. In one embodiment, the patient achieves a clinicalbenefit. In one embodiment, the clinical benefit is one or more ofdecrease in tumor size, suppression or decrease of tumor growth, delayedtime to progression, no new tumor or lesion, a decrease in new tumorformation, an increase in survival or progression-free survival, nometastases, increase in treatment options, delay in time from surgery torecurrence, reduction in jaundice, suppression of spread to liver,reduction in pain, improved appetite, improved digestion, reduction ofgallbladder size, and reduced incidence of blood clots. In oneembodiment, the compound of Formula I is provided as a pharmaceuticalcomposition for oral administration. In one embodiment, the compound isadministered once a day. In one embodiment, the compound is administeredtwice a day. In one embodiment, the effective amount is from 50 mg to300 mg. In one embodiment, the effective amount is 150 mg. In oneembodiment, the method further comprises administering to the patientone or more additional therapeutic compound. In one embodiment, the oneor more additional therapeutic compound is selected from one or more ofa Btk tyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptorinhibitor; an Erbb4 tyrosine kinase receptor inhibitor, an mTORinhibitor, a thymidylate synthase inhibitor, an EGFR tyrosine kinasereceptor inhibitor, an Epidermal growth factor antagonist, a Fyntyrosine kinase inhibitor, a kit tyrosine kinase inhibitor, a Lyntyrosine kinase inhibitor, a NK cell receptor modulator, a PDGF receptorantagonist, a PARP inhibitor, a poly ADP ribose polymerase inhibitor, apoly ADP ribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2inhibitor, a poly ADP ribose polymerase 3 inhibitor, agalactosyltransferase modulator, a dihydropyrimidine dehydrogenaseinhibitor, an orotate phosphoribosyltransferase inhibitor, a telomerasemodulator, a mucin 1 inhibitor, a mucin inhibitor, a secretin agonist, aTNF related apoptosis inducing ligand modulator, an IL17 genestimulator, an interleukin 17E ligand, a Neurokinin receptor agonist, acyclin G1 inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1inhibitor, a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5protein kinase inhibitor, a connective tissue growth factor ligandinhibitor, a notch-2 receptor antagonist, a notch-3 receptor antagonist,a hyaluronidase stimulator, a MEK-1 protein kinase inhibitor MEK-2protein kinase inhibitor, a GM-CSF receptor modulator; TNF alpha ligandmodulator, a mesothelin modulator, an asparaginase stimulator, acaspase-3 stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, ahedgehog protein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wlms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator. In one embodiment, the one or more additionaltherapeutic compound is selected from one or more of bavituximab,IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01,mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps,trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepide,Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib,selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase,varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10,galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct,selinexor, glufosfamide, virulizin, yttrium (90Y) clivatuzumabtetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinbiastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. Inone embodiment, the one or more additional therapeutic compound isFOLFIRINOX. In one embodiment, the one or more additional therapeuticcompounds are gemcitabine and paclitaxel. In one embodiment, the one ormore additional therapeutic compounds are gemcitabine andnab-paclitaxel.Dosing Regimen

Provided herein is a dosing regimen for treating pancreatic cancercomprising administering a compound of Formula I, Ia, Ib or Ic for 6,12, 24 or 48 weeks in combination with Folfirinox or gemcitabine andpaclitaxel or gemcitabine and nab paclitaxel. In some embodiments, thedosing regimen comprises administering a compound of Formula I, la, Ibor Ic for 12 weeks in combination with Folfirinox or gemcitabine andpaclitaxel or gemcitabine and nab paclitaxel. In some embodiments, thedosing regimen comprises administering a compound of Formula Ib for 6,12, 24 or 48 weeks in combination with Folfirinox or gemcitabine andpaclitaxel or gemcitabine and nab paclitaxel. In some embodiments, thedosing regimen comprises administering a compound of Formula Ib for 12weeks in combination with Folfirinox or gemcitabine and paclitaxel orgemcitabine and nab paclitaxel. In some embodiments, the dosing regimencomprises administering a compound of Formula Ib for 12 weeks incombination with Folfirinox.

Provided herein is a dosing regimen for treating pancreatic cancercomprising administering a compound of Formula I, la, Ib or Ic for 6,12, 24 or 48 weeks in combination with Folfirinox or gemcitabine andpaclitaxel or gemcitabine and nab paclitaxel followed by administrationof fluorouracil (5-FU) alone or administration of the compound ofFormula I, Ia, Ib or Ic alone. In some embodiments, the dosing regimencomprises administering a compound of Formula I, Ia, Ib or Ic for 12weeks in combination with Folfirinox or gemcitabine and paclitaxel orgemcitabine and nab paclitaxel followed by administration offluorouracil (5-FU) alone or administration of the compound of FormulaI, Ia, Ib or Ic alone. In some embodiments, the dosing regimen comprisesadministering a compound of Formula Ib for 12 weeks in combination withFolfirinox or gemcitabine and paclitaxel or gemcitabine and nabpaclitaxel followed by administration of fluorouracil (5-FU) alone oradministration of the compound of Formula Ib alone. In some embodiments,the dosing regimen comprises administering a compound of Formula Ib for12 weeks in combination with Folfirinox followed by administration offluorouracil (5-FU) alone or administration of the compound of FormulaIb alone.

Example 1—Method of Treatment

Fifty-four patients age 18 years or older were enrolled on an open-labelphase 1-b interventional study to evaluate the safety and efficacy ofcompound Ib in patients with pancreatic adenocarcinoma also receivingFOLFIRINOX chemotherapy. Dosing consisted of 150 mg tablets for oraladministration once or twice daily given orally for at least 12 weeks.

Inclusion criteria included:

-   -   Histologically or cytologically confirmed non-resectable        pancreatic adenocarcinoma with or without metastases    -   Eastern Cooperative Oncology Group (ECOG) performance status        score ≤2    -   Anticipated life expectancy a ≥12 weeks    -   Radiographically measurable disease acc. to RECIST 1.1    -   Use of adequate contraception (as described in protocol)    -   Ability to provide written informed consent and comply with        study requirements.

Exclusion criteria included:

-   -   Received other cancer treatment or investigational drug within 4        weeks prior to screening    -   Women who are pregnant or breastfeeding    -   Had major surgery within 4 weeks of first dose of study drug    -   Inadequate liver, renal or bone marrow function within 2 weeks        of first dose    -   Serious concurrent illness, altered medical status or any        uncontrolled medical condition    -   Any infection requiring antibiotic or anti-viral treatment        within 4 weeks of screening    -   Known active HIV, HBV or HCV infection    -   Inability to swallow tablets    -   History or presence of any medical condition or disease which,        in the opinion of the investigator, may place the subject at        unacceptable risk for study participation.        Initial 12 week overall response rate (ORR) results:

The open-label, multi-center, Phase Ib clinical trial was designed toevaluate the safety and efficacy of orally administered compound Ib plusFOLFIRINOX in 50 patients with non-resectable pancreatic cancer.Patients received 150 mg of compound Ib twice daily for 12 weeks. After12 weeks, patients who achieved stable disease or better (as measured byResponse Evaluation Criteria In Solid Tumors, or RECIST 1.1), wereeligible to continue on study for at least an additional 12 weeks unlessdisease progression occured. Per protocol, the Eastern CooperativeOncology Group (ECOG) performance status of patients in the trial was 0,1 or 2.

Patients enrolled in the study had advanced non-resectable pancreaticcancer (78% of patients having metastatic disease), and an EasternCooperative Oncology Group (ECOG) Performance Status score of less thanor equal to 2. In order to assess the initial treatment effect ofcompound Ib, the study provided for assessment of overall response rate(ORR) based on computerized tomography (CT) imaging following 12 weeksof treatment.

The pre-specified evaluable ORR population consists of all patients whohave at least one post-baseline disease CT assessment. Response rateresults at 12 weeks of treatment were as follows:

Pre-Specified ITT Evaluable Patient Patient Population Population¹ (N =41) (N = 50) Tumor control rate² 32/41 (78%) 32/50 (64%) Overallresponse rate³ 15/41 (37%) 15/50 (30%) Stable disease 17/41 (41%) 17/50(34%) Progressive disease  9/41 (22%)  9/50 (18%) Not evaluable⁴  9/50(18%) ¹Pre-specified as the primary efficacy population = pre-defined asall patients who have a least one post baseline CT scan. ITT = allpatients randomized, including those with no post baseline CT scan.²Tumor control rate includes stable disease, partial response andcomplete response. ³Overall response rate measured by ResponseEvaluation Criteria for Solid Tumors version 1.1 (RECIST 1.1). Allresponses included in ORR were partial responses (PRs). ⁴Not evaluabledue to no post baseline CT scan due to early withdrawal.

Compound Ib was well tolerated by advanced pancreatic cancer patients.The incidence and rate of adverse events were consistent with datareported historically for FOLFIRINOX alone, suggesting no apparentadditional safety burdens of combining compound Ib with FOLFIRINOX.

Example 2—Pharmacokinetic Parameters of Compound Ib and PF-04136309 inSprague-Dawley Rats

Compound Ib and PF-04136309 were dosed intravenously at 0.5 mg/kg andorally at 2 mg/kg, in aqueous hydroxypropyl methylcellulose. Bloodsamples were collected at predetermined time points after each dosingand the corresponding plasma concentrations of Compound Ib andPF-04136309 were analyzed using an LC-MS/MS method. Plasmaconcentration-time curves were constructed and the correspondingpharmacokinetic parameters were derived using non-compartmentalanalysis.

Blood (0.2 mL) was sampled through the jugular vein or cardiac puncture(for terminal point only) at pre-dose, 2, 5, 10, 15, and 30 min, 1, 2,4, 6, and 8 hours post-dose for i.v. dosing and at pre-dose, 5, 15, and30 min, 1, 1.5, 2, 4, 6, and 8 hours post-dose for oral dosing. Bloodsamples were collected into chilled polypropylene tubes containingsodium EDTA as the anticoagulant and plasma was collected throughcentrifugation (Eppendorf Centrifuge 5417R) at 10,000 rpm and 4° C. for6 minutes and stored at −20° C. until analysis.

Plasma samples (50 μL) were extracted with 200 μL acetonitrilecontaining the internal standard on a linear shaker for 10 min and thencentrifuged at 3700 g for 10 min at 4° C. (Allegra X-15R centrifuge,Beckman Coulter, Inc., Fullerton, Calif.). 100 μL of the resultingsupernatant was transferred into a new plate and mixed with 100 μL 0.1%formic acid in water for LC-MS/MS analysis.

Calibration standard samples were prepared with blank Sprague-Dawley ratplasma, at 5000, 2500, 1000, 500, 100, 50, 20, 10, 4, 2 and 1 ng/mL ofcompound. Three levels of the standard stock solutions (1000, 100 and 10ng/mL) were spiked separately into male Sprague-Dawley rat plasma andused as QC samples. Plasma standards and QC samples were treatedidentically and prepared in parallel with the plasma samples. Extractedsamples were analyzed by LC-MS/MS.

Mass spectrometer acquisition and integration were performed withApplied Biosystems-Sciex Analyst software (version 1.4.2). Thecalibration curve was obtained through a quadratic regression and thecalibration range was 2-5000 ng/mL.

Instrument:

-   -   API 3000 mass spectrometer (Applied Biosystems, Foster City,        Calif.)    -   Agilent 1100 HPLC binary pump (Santa Clara, Calif.)    -   LEAP Technologies HTS Pal Autosampler (Carrboro, N.C.)    -   Thermo Scientific Cohesive Aria LX-2 duplexing system (Waltham,        Mass.)        Column: Zorbax Eclipse XDB Phenyl 2.1×50 mm (Agilent, Santa        Clara, Calif.)        Injection Volume: 10 μL        Flow Rate: 0.60 mL/min

TABLE 1 HPLC Gradient Mobile Phase A-0.1% Mobile Phase B-0.1% Time (min)formic acid in water formic acid in acetonitrile 0 98 2 0.08 98 2 1.58 298 2.58 2 98 2.67 98 2 3.50 98 2

Ionization Mode: Electrospray (ESI). Detection Mode: Positive MRM. Foreach dosing route, descriptive pharmacokinetic parameters weredetermined by a standard non-compartmental analysis (Wagner, 1993) fromthe plasma concentration-time curve. Pharmacokinetic analysis wasperformed by using XLFit® v.4.3.1 (ID Business Solutions Inc., Alameda,Calif.) in conjunction with Microsoft Excel 2003.

TABLE 2 Pharmacokinetic parameters of compound lb and PF-04136309 inSprague-Dawley rats Compound lb PF-04136309 Rat PK Clearance 11.5mL/min/kg 71.1 mL/min/kg (iv, 0.5 mg/kg) AUC 3,910 ng*hr/mL 111 ng*hr/mL(po, 2 mg/kg) Oral Bioavailability 133% 22%

Compared to PF-4136309, compound Ib has a much lower clearance and muchhigher exposure (AUC).

Example 3—Pharmacokinetic Parameters of Compound Ib in Beagle Dogs

The pharmacokinetic profile of compound Ib was evaluated in male beagledogs following intravenous (i.v.) and oral (p.o.) administration. Asingle dose of compound Ib was dosed intravenously at 0.5 mg/kg andorally at 2 mg/kg. Blood samples were collected at predetermined timepoints after each dosing and the corresponding plasma samples wereanalyzed using an LC-MS/MS method. Plasma concentration-time curves wereconstructed using the plasma concentrations and the correspondingpharmacokinetic parameters were derived by non-compartmental analysis.

Six animals weighing 11.5, 9.9, 9.9, 14.6, 11.1, and 9.8 kg,respectively, were used with Compound Ib dosed intravenously at 0.5mg/kg (the first 3 animals) and orally at 2 mg/kg (the second 3animals).

For i.v. dosing, a solution formulation of Compound Ib was prepared in36.8% water/31.6% propylene glycol/31.6% N,N-dimethyl acetamide at 0.5mg/mL and each animal received 1 mL/kg. For oral dosing at 2 mg/kg, asolution formulation was prepared in 1% hydroxypropyl methylcellulose at0.5 mg/mL and each animal received 4 mL/kg.

For dosing, blood (˜1 mL) was drawn at pre-dose and at 5, 15, and 30min, 1, 2, 4, 8, 12, and 24 hours post-dose. Blood was sampled from theforeleg vein via butterfly catheter and then placed into chilledpolypropylene tubes containing K2EDTA as the anticoagulant and kept onice until centrifugation. Plasma was collected through centrifugationand shipped on dry ice for sample analysis.

Plasma samples (50 μL) were extracted with 200 μL 0.1% formicacid/acetonitrile containing the internal standard on a linear shakerfor 10 min and then centrifuged at 3700 g for 10 min at 4° C. (AllegraX-15R centrifuge, Beckman Coulter, Inc., Fullerton, Calif.). 100 μL ofthe resulting supernatant was transferred into a new plate and mixedwith 100 μL 0.1% formic acid in water for LC-MS/MS analysis.

Calibration standard samples were prepared with blank dog plasma, at5000, 2500, 1000, 500, 100, 50, 20, 10, 4, 2 and 1 ng/mL of Compound Ib.Three levels of the standard stock solutions (1000, 100 and 10 ng/mL)were spiked separately into male beagle dog plasma and used as QCsamples. Plasma standards and QC samples were treated identically andprepared in parallel with the plasma samples.

Sample analysis was performed by LC-MS/MS (details shown below).Acquisition and peak integration were performed with the AppliedBiosystems-Sciex Analyst software (version 1.4.2). Calibration curveswere obtained through quadratic regression with a weighting of 1/x. Thecalibration range was 1-5000 ng/mL.

Instrument:

-   -   Applied Biosystems API 3000 mass spectrometer (Foster City,        Calif.)    -   Agilent 1100 HPLC binary pump (Santa Clara, Calif.)    -   LEAP Technologies HTS Pal Autosampler (Carrboro, N.C.)    -   Thermo Scientific Cohesive Aria LX-2 duplexing system (Waltham,        Mass.)        Column: Zorbax Eclipse XDB Phenyl 2.1×50 mm (Agilent, Santa        Clara, Calif.)        Injection Volume: 10 μL        Flow Rate: 0.60 mL/min

TABLE 3 HPLC Gradient Mobile Phase A Mobile Phase B 0.1% formic acid in0.1% formic acid in Time (min) water acetonitrile 0 98 2 0.08 98 2 1.582 98 2.58 2 98 2.67 98 2 3.50 98 2Ionization Mode: Turbo Ionspray ESIDetection Mode: Positive MRMFor each dosing route, descriptive pharmacokinetic parameters weredetermined by a standard non-compartmental analysis (Wagner, 1993) fromthe plasma concentration-time curve.

-   -   CL: Total body clearance    -   AUC: area under the curve    -   F: Bioavailability.

Pharmacokinetic analysis was performed by using XLFit® v.4.3.1 (IDBusiness Solutions Inc., Alameda, Calif.) in conjunction with MicrosoftExcel 2003.

TABLE 4 Mean pharmacokinetic parameters of Compound lb and PF-04136309following i.v. and oral dosings of lb (N = 3) PF-04136309 (dataextracted from ACS Med. Chem. Compound lb Lett. reference) Dog PKClearance 0.7 (dosed at 0.5 7.6 (dosed at 2 iv mg/kg) mg/kg) AUC po67000 ng*hr/mL 20198 ng*hr/mL (dosed at 2 mg/kg) (dosed at 10mg/kg) Oral143% (dosed at 2 78% (dosed at Bioavailability mg/kg) 10mg/kg)

The pharmacokinetics parameters of PF-4136309 were disclosed in ACS Med.Chem. Lett. 2011, 2, 913-918.

Compared to PF-4136309, compound Ib has a much lower clearance and muchhigher exposure (AUC) at comparable doses.

FIG. 1 represents the mean plasma concentration of Compound Ib followingi.v. dosing in dog of Compound Ib.

FIG. 2 represents the mean plasma concentration of Compound Ib followingp.o. dosing in dog of Compound Ib.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present disclosure.

Although specific embodiments of the present disclosure are hereinillustrated and described in detail, the disclosure is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present disclosure and should not be construed as constituting anylimitation of the disclosure. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the disclosure are intended to be included with the scope ofthe appended claims.

What is claimed is:
 1. A method for controlling an adenocarcinoma in apatient comprising administering to the patient in need thereof aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is halogen orC₁₋₆ alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or —CN; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, halogen, or C₁₋₆ alkyl; each R⁵ is independentlyC₁₋₆ alkyl, —OH, or —NH₂; n is 0, 1, 2, or 3; and each of A¹, A², and A³is —CH— or —N—, where at least one of A¹, A², or A³ is —N—.
 2. Themethod of claim 1, wherein R¹ is halogen or methyl; R² is halogen orC₁₋₆ haloalkyl; R³ is halogen or C₁₋₆ alkyl; R⁴ is hydrogen; n is 0; A¹is —CH— or —N—; A² is —CH—; and A³ is —N—.
 3. The method of claim 1,wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the adenocarcinoma is pancreatic adenocarcinoma.
 6. The methodof claim 1, wherein the patient achieves a complete response.
 7. Themethod of claim 1, wherein the patient achieves a partial response. 8.The method of claim 1, wherein the patient achieves stable disease. 9.The method of claim 1, wherein the patient achieves a slower progressivedisease.
 10. The method of claim 1, wherein the patient achieves aclinical benefit.
 11. The method of claim 10, wherein the clinicalbenefit is one or more of decrease in tumor size, suppression ordecrease of tumor growth, delayed time to progression, no new tumor orlesion, a decrease in new tumor formation, an increase in survival orprogression-free survival, no metastases, increase in treatment options,delay in time from surgery to recurrence, reduction in jaundice,suppression of spread to liver, reduction in pain, improved appetite,improved digestion, reduction of gallbladder size, and reduced incidenceof blood clots.
 12. The method of claim 1, wherein the compound ofFormula I is provided as a pharmaceutical composition for oraladministration.
 13. The method of claim 1, wherein the compound isadministered once a day.
 14. The method of claim 1, wherein the compoundis administered twice a day.
 15. The method of claim 1, wherein theeffective amount is from 50 mg to 300 mg.
 16. The method of claim 1,wherein the effective amount is 150 mg.
 17. The method of claim 1,further comprising administering to the patient one or more additionaltherapeutic compound.
 18. The method of claim 17 wherein the one or moreadditional therapeutic compound is selected from one or more of a Btktyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptor inhibitor;an Erbb4 tyrosine kinase receptor inhibitor, an mTOR inhibitor, athymidylate synthase inhibitor, an EGFR tyrosine kinase receptorinhibitor, an Epidermal growth factor antagonist, a Fyn tyrosine kinaseinhibitor, a kit tyrosine kinase inhibitor, a Lyn tyrosine kinaseinhibitor, a NK cell receptor modulator, a PDGF receptor antagonist, aPARP inhibitor, a poly ADP ribose polymerase inhibitor, a poly ADPribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2 inhibitor,a poly ADP ribose polymerase 3 inhibitor, a galactosyltransferasemodulator, a dihydropyrimidine dehydrogenase inhibitor, an orotatephosphoribosyltransferase inhibitor, a telomerase modulator, a mucin 1inhibitor, a mucin inhibitor, a secretin agonist, a TNF relatedapoptosis inducing ligand modulator, an IL17 gene stimulator, aninterleukin 17E ligand, a Neurokinin receptor agonist, a cyclin G1inhibitor, a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor,a CTLA4 inhibitor, a topoisomerase I inhibitor, an Alk-5 protein kinaseinhibitor, a connective tissue growth factor ligand inhibitor, a notch-2receptor antagonist, a notch-3 receptor antagonist, a hyaluronidasestimulator, a MEK-1 protein kinase inhibitor; MEK-2 protein kinaseinhibitor, a GM-CSF receptor modulator; TNF alpha ligand modulator, amesothelin modulator, an asparaginase stimulator, a caspase-3stimulator; caspase-9 stimulator, a PKN3 gene inhibitor, a hedgehogprotein inhibitor; Smoothened receptor antagonist, an AKT1 geneinhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29modulator, a fibronectin modulator, an interleukin-2 ligand, a serineprotease inhibitor, a D40LG gene stimulator; TNFSF9 gene stimulator, a2-oxoglutarate dehydrogenase inhibitor, a TGF-beta type II receptorantagonist, an Erbb3 tyrosine kinase receptor inhibitor, acholecystokinin CCK2 receptor antagonist, a Wilms tumor proteinmodulator, a Ras GTPase modulator, an histone deacetylase inhibitor, acyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptorbeta modulator, a 4-1 BB inhibitor, a 4-1BBL inhibitor, a PD-L2inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, aHVEM inhibitor, aTIM3 inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, aVISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor anda CD66e modulator.
 19. The method of claim 17 wherein the one or moreadditional therapeutic compound is selected from one or more ofbavituximab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K,PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207,NovaCaps, trametinib, Atu-027, sonidegib, GRASPA, trabedersen,nastorazepide, Vaccell, oregovomab, istiratumab, refametinib,regorafenib, lapatinib, selumetinib, rucaparib, pelareorep, tarextumab,PEGylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01,GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab,DCVax-Direct, selinexor, glufosfamide, virulizin, yttrium (90Y)clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L,tegafur+gimeracil+oteracil potassium+calcium folinate, olaparib,ibrutinib, pirarubicin, Rh-Apo2L, tertomotide,tegafur+gimeracil+oteracil potassium, tegafur+gimeracil+oteracilpotassium, masitinib, Rexin-G, mitomycin, erlotinib, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, platinum derivatives, taxane, paclitaxel, vincaalkaloids, vinblastine, anthracyclines, doxorubicin,epipodophyllotoxins, etoposide, cisplatin, rapamycin, methotrexate,actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents, chlorambucil, 5-fluorouracil, campthothecin,cisplatin, metronidazole, Gleevec, Avastin, Vectibix, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine,AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin,bortezomib, busulfan, calusterone, capecitabine, camptothecin,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine,clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin(neutral), doxorubicin hydrochloride, dromostanolone propionate,epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, rociletinib,sargramostim, sorafenib, streptozocin, sunitinib maleate, talc,tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine,6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab,IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001,GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559,ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX and KY-1003. 20.The method of claim 17, wherein the one or more additional therapeuticcompound is FOLFIRINOX.
 21. The method of claim 17, wherein the one ormore additional therapeutic compounds are gemcitabine and paclitaxel.